SUMMARY At least half of individuals with fragility fractures have normal bone mass, highlighting a role for bone quality determinants such as the material properties of the bone extracellular matrix, among others. However, the control of bone quality is poorly understood, relative to bone mass. This gap in understanding has limited the development of therapeutics for bone fragility caused by defects in bone quality. Recently, perilacunar remodeling (PLR) by osteocytes has been shown to play a pivotal role in maintaining bone quality. The TGF? pathway functions in osteoblasts and osteoclasts to maintain bone mass, but it is also a crucial participant in skeletal mechanotransduction and is the most well-defined regulator of bone quality. Preliminary results using a novel mouse model highlight the critical role of osteocyte-intrinsic TGF? signaling in PLR and bone quality. Because an osteocyte-specific ablation in TGF? signaling represses several genes implicated in PLR, we considered the possible role of microRNAs (miRs), which post-transcriptionally regulate gene expression and can coordinately target gene networks to induce or repress entire cell programs. This led to the hypothesis that miRs coordinately regulate osteocyte PLR in a TGF?- and mechano-sensitive manner. New preliminary data and bioinformatics analyses support the involvement of a specific miR cluster in this regulatory network. In addition to evaluating the functional role of this compelling candidate and other identified TGF?-responsive miRs, this proposal uses an unbiased expression profiling approach to identify novel miR/mRNA networks that participate in the TGF?-mediated loading response. Specifically, Aim 1 seeks to identify miRs that participate in the osteocytic response to TGF? using a combination of in vivo and in vitro model systems. Aim 2 employs unbiased and candidate approaches to determine the regulation and role of osteocyte miRs in mechanosensitive TGF? signaling. Genomic analysis of miRs and mRNA targets in osteocyte mechanotransduction will elucidate new post-transcriptional regulatory networks. Together with the proposed candidate approach, these studies will (i) elucidate the miR-100 mediated mechanism by which mechanical stimuli impact TGF? signaling to maintain skeletal homeostasis and (ii) delineate other important miR families responsive to load and TGF?. Given the promise of miR-based therapeutics, these studies have the potential to identify novel targets for the development of much needed diagnostics and therapies for the treatment of bone fragility due to bone quality defects.